This invention relates to the composition of chemodenervating agents used for the treatment of diseases. The invention offers an improvement on the prior art by eliminating the muscle-weakening side effect of prior-art chemodenervating agents. This is achieved by eliminating the neurotoxin component of the chemodenervating agent.
Migraine and tension headaches are a major cause of loss of productivity for those afflicted, usually due to pain and associated systemic symptoms. The syndrome of migraine and other essential headaches is characterized by severe throbbing headaches often made worse by physical activity and associated with aversion to light and sound. The syndrome often, but not always, includes nausea and/or sometimes vomiting as major components. The pain is often unilateral or localized to a portion of the head. The condition is episodic in nature, with episodes typically lasting 4-72 hours.
Tension headache is the most common type of essential headache and is characterized by head pain not associated with any structural lesions, often not associated with nausea, and occurring more frequently and less episodically than migraine headache.
Recently botulinum toxin injections within the head and neck region have been advocated as a method to treat migraine headache, tension headache, and myofascial pain, both acutely and for prophylaxis. Efficacy for both myofascial pain and migraine headaches has been shown in double-blind placebo-controlled trials. However, the mechanism of action has not been clearly explained, as botulinum toxin has been thought to exert its beneficial effects for most indications by causing decreased muscle tone and contractility. The major limiting factor involved in injecting botulinum toxin is the muscle-weakening effect. For instance, ptosis (drooping of the upper eyelid) is the major side effect caused by the injection of neurotoxin for the treatment of human headache disorders. This results from the neuromuscular paralytic effects of the neurotoxin component of the botulinum toxin molecule.
Recently, the present inventor has shown botulinum toxin to have anti-inflammatory components, both in vivo in man and in animal experiments. This unique property has not been previously appreciated or defined and in fact may explain the mechanism of action by which botulinum toxin exerts its beneficial effects in essential headache disorders (migraine and tension headaches) as well as in other medical conditions. Evidence that botulinum toxin acts on the inflammatory response associated with essential headaches can be categorized into clinical observations and animal experiments as disclosed herein.
A limiting property of botulinum toxin for the treatment of pain or inflammatory disease relates to its weakening effect on muscle tissue caused by blocking acetylcholine release by its neurotoxin component. The utility of the invention described herein is based upon a compositional change to the botulinum exotoxin proteins used in medical practice that eliminates neurotoxin activity, while maintaining a biological activity that is capable of suppressing pain and inflammation. Such compositional improvement allows the exotoxin protein to be used without the attendant risk of inducing muscle atrophy and weakness, while retaining a biological effect useful for the clinical relief-of pain and discomfort.